Andy Watts - Basic principles of drug design

Question 1

What are the steps involved from identifying a disease to pre clinical testing? (7)

Answer 1

1) Identify disease
2) Isolate a protein (Genomics, proteomics and biopharm) - Producing more tagets and personalised targets
3) HTS - Screen many samples of compounds for activity against target protein
4) Virtual screening - use computer to predict activity
5) Combinatorial chem - Rapidly produce vast numbers of compounds to test
6) Molecular modelling - Computer graphics and models help improve activity (dock molecule into enzyme and improve structure and binding)
7) Pre clinical testing using In vitro and in silico adme models - tissue and computer models begin to replace animal testing

Question 2

List some suitable chemical properties that drug molecules need…

List some suitable biological properties that drug molecules need…

List some general favourable properties in relation to administration…

Answer 2

1)
Chemical stability
Solubility
pKa

2)
Biodistribution 
Metabolism
Solubility 
Potency
Specificity 
Toxicity 

Appropriate route of admin (solubility and metab)
Appropriate dosage (amount/freq)
Appropriate formulation (solubility and admin)

Question 3

A drug molecule may be conceptualised as a collection of molecular fragments, or building blocks.
The most important of these is the _____, being displayed on a molecular ____ composed of metabolically ____ and conformationally ____ structural units

Answer 3

1) Pharmacophore
2) Framework
3) Inert
4) Restrained

Question 4

What is a pharmacophore?

Answer 4

• Atoms and functional groups required for specific pharmacological activity, and their relative positions in space

Question 5

What is Genomics?

Answer 5

• Understanding of how DNA, genes, proteins and protein function are related, in both normal and disease states
• Human genome project mapped genes in human DNA
• Hope to find more protein targets
• Allows personalisation of therapy (e.g see likelihood of developing disease - cancer, and take steps needed to prevent onset)

Question 6

What is High Throughput Screening?

Answer 6

• Test 100,000 compounds a day for activity against protein target
• Many may show activity for protein
• Select a few classes of compounds that show most promise for being drugs to follow up
• Carry out additional work on these compound classes

Question 7

What is combinatorial chemistry?

Answer 7

• Techniques for producing large numbers of compounds in a short period of time
• Uses defined reaction routes and large variety of starting materials and reagents
• Usually involves a scaffold molecule and sets of compounds which can be reacted with the scaffold to place different structures on attachment points (add diff R groups)

Question 8

Outline protein crytstallography

Answer 8

• Take target and crystallise it
• Take X-ray through crystals
• Analyse the defraction patterns to produce a 3D map of atoms in the protein
• A protein structure image is produced which can be analysed

Question 9

What can be used to provide a 3D visualisation of proteins and bound compounds?

Answer 9

• 3D visualisation of structure of protein and bound compounds
• Produced using X-ray crystallography and NMR spectroscopy
• Can visualise the complexes of these proteins and potential drugs
• Helps scientists understand mechanism of action of drug and to improve design of drug
• Visualisation uses computational ball and stick models of atoms and bonds, as well as surfaces

Question 10

What is molecular modelling?

Answer 10

• 3D visualisation of interactions between compounds and proteins
• Docks compounds into proteins computationally
• See how molecules interact with protein active site through binding

Question 11

What is docking with a generic algorithm?

Answer 11

• Put compound in approximate area where binding occurs
• Generic algorithm encodes orientation of compound and rotatable bonds to see how drug fits target
• Then optimises binding to the protein by finding…
  Minimum energy, hydrogen bonding, hydrophobic interactions
• Can be used for virtual screening to predict what structure gives highest affinity of drug
• Helps reduce number of compounds needed to be made

Question 12

Molecular modelling can involve receptor surface analysis. What is this?

Answer 12

• Find different sites on receptors to see which groups on a drug compound may interact
• e.g hydrophobic areas, acidic areas
• Can see unfavourable and favourable drug-receptor surface interaction sites
• Can then optimise binding of drug in its receptor by introducing appropriate pharmacophores onto scaffold

Question 13

Why are In Vitro and In Silico ADME models more frequently used now?

Answer 13

• Animal tests are expensive, time consuming and ethically undesirable
• ADME model techniques help us to model how the drug is likely to act in body
• Methods can be experimental (in vitro) using cellular tissue or in silico using computational methods
• Can look at PK and PD to see toxicity

Question 14

Briefly describe use of In Vitro ADME models…

Give an example.

Answer 14

• Based on real tissue samples, with similar properties to those in the body
• e.g CACO-2 tissue resembles stomach lining so if can pass molecule through CACO-2, likely to be able to also pass through stomach lining so candidate for oral delivery
• Cuts down animal tests as acts as a pre-screen
• Allows us to collect more ADME data

Question 15

Briefly describe use of In Silico ADME models…

Give an example.

Answer 15

• Computational methods used to predict compound properties important to ADME e.g.
• LogP (liphophilicity)
• Solubility
• Permeability
• Cytochrome P450 metabolism
• Can make estimates for millions of compounds to reduce attrition in later stages (can rule out those with unfavourable ADME properties early)